Accelerated Fractionated Radiation Therapy for Localized Glottic Carcinoma.

BACKGROUND: The aim of this study is to examine the outcomes of an accelerated fractionated irradiation for N0 glottic carcinoma. METHODS: In this retrospective analysis, 29 patients with N0 glottic carcinoma treated by radiation therapy were enrolled. Thirteen patients had T1a disease, six had T1b disease, and ten had T2 disease. A fractional dose of 2.1 Gy was administered to seven patients. The total doses were 65.1 and 67.2 Gy in four and three patients, respectively. A fractional dose of 2.25 Gy was administered to 22 patients. The total doses were 63 and 67.5 Gy in 21 patients and 1 patient with T2 disease, respectively. Additionally, 13 patients underwent the use of TS-1 (80-100 mg per day). RESULTS: The median follow-up period was 33 months, and the 3-year local control rate was 95.6%. No patient had a lymph node or distant recurrence. As acute adverse events, grades 2 and 3 dermatitis were observed in 18 patients and 1 patient, and grades 2 and 3 mucositis were observed in 15 patients and 1 patient. As a late adverse event, one patient required tracheotomy because of laryngeal edema occurring. CONCLUSIONS: Accelerated fractionated irradiation may be an option in the radiation therapy of N0 glottic carcinoma because of its ability to shorten the treatment time.

Carbon-ion radiotherapy for inoperable upper tract ureteral cancer.

AIM: This study aimed to report initial results of hypofractionated carbon-ion radiotherapy (C-ion RT) for inoperable upper tract ureteral cancer. METHODS: Retrospective chart review was performed for five consecutive patients with medically inoperable ureter cancer that was treated with radical C-ion RT between December 2013 and December 2014. The median age of the patients was 80 years (range, 68-84 years). The reasons for inoperability were advanced age, post-contralateral nephrectomy, alcoholic cirrhosis, both advanced age and contralateral renal function degeneracy, and pneumonia. The median size of tumor was 2.8 cm (range, 2.2-4.0 cm). Diagnostic imaging did not identify lymph node metastases or distant metastases in any case. All patients underwent C-ion RT (52.8 Gy relative biological effectiveness; 12 fractions in 3 weeks). The clinical target volume encompassed the growth tumor volume with a 5-mm margin bilaterally; there was a 40-mm margin craniocaudally but the clinical target volume did not encompass the whole ureter. RESULTS: Within a median follow-up time of 32.9 months (range, 24-36 months), two patients died and three remained alive. Neither local recurrence nor regional lymph node metastases were observed. Secondary bladder tumor was observed in four patients, and one patient had a liver metastasis. Grade 1 hematuria was observed in two patients, and Grade 3 pyelonephritis was observed in one patient as acute toxicity. Ureteral obstruction was observed in two patients. CONCLUSION: C-ion RT might be a useful treatment option for inoperable ureter cancer.

Efficacy of immune checkpoint inhibitor treatment for head and neck mucosal melanoma recurrence in patients treated with carbon-ion radiotherapy.

BACKGROUND: Carbon-ion radiotherapy (C-ion RT) is effective for head and neck mucosal melanoma (HN-MM), including radioresistant mucosal melanoma. Melanoma also responds effectively to immune checkpoint inhibitors (ICIs). Data on the efficacy and safety of ICIs for HN-MM are insufficient. AIMS: To analyze the efficacy and safety of ICI salvage therapy in patients with HN-MM recurrence after C-ion RT. METHODS AND RESULTS: This retrospective study analyzed the medical records of 52 patients with HN-MM treated with C-ion RT between 2012 and 2020. A dose of 57.6 or 64.0 Gy (relative biological effectiveness) was provided in 16 fractions. The primary endpoint was 3-year overall survival (OS) rate. The median follow-up time was 26.8 months for all patients. A total of 29 patients had local recurrence or distant metastasis, and 16 patients who received ICI therapy. The 3-year OS rate in the ICI group (n = 16) and best supportive care group (n = 13) were 53.8% and 0.0%, respectively (p = 0.837); the difference was not statistically significant. There were no deaths after 1 year among patients who underwent ICI therapy. No adverse events associated with C-ion RT were related to or exacerbated by ICI. CONCLUSION: ICI salvage therapy is effective and safe for patients with HN-MM recurrence after C-ion RT.

Isofraxidin enhances hyperthermia­induced apoptosis via redox modification in acute monocytic leukemia U937 cells.

The cell­killing potential of most chemotherapeutic agents is enhanced by a temperature elevation. Isofraxidin (IF) is a coumarin compound widely found in plants, such as the Umbelliferae or Chloranthaceae families. IF induces anticancer effects in lung and colorectal cancer. To the best of our knowledge, the combined effects of hyperthermia (HT) and IF on heat­induced apoptosis have not been reported. Acute monocytic leukemia U937 cells were exposed to HT with or without IF pre­treatment. Apoptosis was measured by Annexin V­FITC/PI double staining assay using flow cytometry and cell viability was observed by cell counting kit assay, DNA fragmentation. The mechanism involved in the combination was explored by measuring changes in the mitochondrial membrane potential, (MMP), intracellular ROS generation, expression of apoptosis related protein, and intracellular calcium ion level. It was demonstrated that IF enhanced HT­induced apoptosis in U937 cells. The results demonstrated that combined treatment enhanced mitochondrial membrane potential loss and transient superoxide generation increased protein expression levels of caspase­3, caspase­8 and phosphorylated­JNK and intracellular calcium levels. Moreover, the role of caspases and JNK was confirmed using a pan caspase inhibitor (zVAD­FMK) and JNK inhibitor (SP600125) in U937 cells. Collectively, the data demonstrated that IF enhanced HT­induced apoptosis via a reactive oxygen species mediated mitochondria/caspase­dependent pathway in U937 cells.

Carbon-ion Radiotherapy for Inoperable Head and Neck Bone and Soft-tissue Sarcoma: Prospective Observational Study.

BACKGROUND/AIM: Bone and soft-tissue sarcomas of the head and neck have very poor prognoses. This prospective study aimed to investigate the efficacy and safety of carbon-ion radiotherapy (C-ion RT) for bone and soft-tissue sarcoma of the head and neck. PATIENTS AND METHODS: The present study was a prospective clinical study that included 10 consecutive patients diagnosed with bone and soft-tissue sarcoma of the head and neck who were treated with C-ion RT between 2012 and 2018 at our institution. C-Ion RT consisted of 70.4 Gy (relative biological effectiveness) in 16 fractions. RESULTS: The 3-year local control, overall survival, and progression-free survival rates for patients overall were 72.9%, 77.8%, and 36%, respectively. CONCLUSION: The present study demonstrated the efficacy of C-ion RT for bone and soft-tissue sarcoma of the head and neck; adverse events were within the expected range.

Efficacy and Safety of Carbon-Ion Radiotherapy for Stage I Non-Small Cell Lung Cancer with Coexisting Interstitial Lung Disease.

Interstitial lung disease (ILD) is a risk factor both for the development and treatment failure of lung cancer. In this retrospective study, we analyzed the outcome of carbon-ion radiotherapy (CIRT) in 124 patients with clinical stage I non-small cell lung cancer (NSCLC), of whom 26 (21%) had radiological signs of pre-existing ILD. ILD was diagnosed retrospectively by a pulmonologist based on critical review of CT-scans. Ninety-eight patients were assigned to the non-ILD group and 26 patients (21.0%) to the ILD group. There were significant differences in pre-treatment KL-6 values between the two groups. The three year overall survival and cause-specific survival rates were 83.2% and 90.7%, respectively, in the non-ILD group, and 59.7% and 59.7%, respectively, in the ILD group (between-group differences, p = 0.002 and p < 0.001). Radiation pneumonitis worse than Grade 2 was observed in three patients (3.0%) in the non-ILD group and two patients (7.6%) in the ILD group (p = 0.29). There were no cases of acute exacerbation in the ILD group. CIRT for stage I NSCLC was as safe in the ILD group as in the non-ILD group. Coexisting ILD was a poor prognostic factor in CIRT for clinical stage I lung cancer.

Clinical features and dosimetric evaluation of carbon ion radiation-induced osteoradionecrosis of mandible in head and neck tumors.

BACKGROUND AND PURPOSE: Osteoradionecrosis (ORN) affects the patient's quality of life by making eating and maintaining oral hygiene painful. This study aimed to analyze carbon ion radiotherapy (C-ion RT)-induced ORN of the mandible. MATERIALS AND METHODS: A retrospective study of 199 patients with head and neck tumors treated with C-ion RT was performed from 2010 to 2019. Only 11 patients with tumors located in the oropharynx and floor of the mouth were analyzed. C-ion RT consisted of 57.6 Gy or 64.0 Gy (relative biological effectiveness) in 16 fractions. The mandible was analyzed for magnetic resonance imaging (MRI) changes and bone exposure. The relationship between the radiation dose and ORN of the mandible was analyzed. RESULTS: Five patients (45.5%) had ORN of the mandible. The median follow-up time was 68 months. The median onset times based on MRI changes and bone exposure were 9 and 15 months, respectively. Doses of 30 Gy (relative biological effectiveness) to the mandible and teeth showed the most significant effect, causing ORN at 29.5 ± 6.7 cc and 3.9 ± 1.8 cc, respectively, with cut-off values at 16.5 cc (p = 0.002) and 1.8 cc (p = 0.0059), respectively. CONCLUSION: This is the first study reporting the incidence, onset time, and risk-predictive dosimetry parameters of C-ion RT-induced ORN of the mandible. Our study will be useful for establishing clinical strategies for C-ion RT to the head and neck near the mandible.

Multicenter Study of Carbon-ion Radiotherapy for Oropharyngeal Non-squamous Cell Carcinoma.

BACKGROUND/AIM: To evaluate treatment outcomes of carbon-ion radiotherapy for oropharyngeal non-squamous cell carcinoma at four carbon-ion facilities in Japan. PATIENTS AND METHODS: We retrospectively analyzed the cases of 33 patients with oropharyngeal non-squamous cell carcinoma who were treated with carbon-ion radiotherapy between November 2003 and December 2014. RESULTS: The histology included adenoid cystic carcinoma (n=25) and mucosal malignant melanoma (n=4). No patients had T1 tumors; 23 had T4 tumors. The most-commonly prescribed dose was 57.6 Gy (RBE) in 16 fractions. The median follow-up period was 34.8 months (range=4.2-122.8 months). The 3-year local control and overall survival rates were 94.7% and 90.7%, respectively. There were no grade ≥4 acute adverse events. Only one patient experienced a grade ≥4 late adverse event. No patients experienced late adverse events related to swallowing or salivary function. CONCLUSION: Carbon-ion radiotherapy appears to be a promising treatment option for oropharyngeal non-squamous cell carcinoma.

Stereotactic body radiotherapy for adenoid cystic carcinoma metastatic to the lung: a case report.

BACKGROUND: Adenoid cystic carcinoma (ACC) is a rare malignant tumor involving mostly the head and neck region, and frequently the salivary glands. The development of lung metastasis after treatment of the primary tumor is a common occurrence in ACC. Although lung metastases show a slow rate of growth, approximately 10% of patients die from distant metastases. The radioresistance of ACC limits the efficacy of conventional radiotherapy for lung metastases, and the optimal dose remains to be determined. Stereotactic body radiotherapy (SBRT) using CyberKnife can deliver a high dose to the lung tumor, while sparing the surrounding normal lung tissues, leading to favorable local control in non-squamous cell lung cancer and metastatic lung tumors. We report a case of lung metastases from ACC treated successfully with SBRT using CyberKnife. CASE PRESENTATION: A 76-year-old Japanese man with ACC who was treated with carbon ion radiotherapy for a primary oropharynx tumor presented with three metastatic lesions in the lung. The tumor masses were located in the right upper, right lower, and left lower lobes of the lungs. Surgical resection was not indicated because of the presence of multiple tumors. The patient underwent SBRT at 60 Gy in 10 sequential fractions for each tumor. The biologically effective dose based on an alpha/beta ratio of 2 Gy was 240 Gy per tumor. The percentage of the total lung volume irradiated with >20 Gy was 4.9%, 3.2%, and 2.6% for each tumor. The patient developed acute radiation pneumonitis during the initial therapy, which resolved at 6 months after the CyberKnife treatment. At 21 months after the first CyberKnife treatment, three tumors showed no signs of recurrence. No late toxicity was observed. CONCLUSIONS: SBRT using CyberKnife is an effective and feasible approach to the management of multiple lung metastases of ACC.

Comparison of Oncologic Outcomes between Carbon Ion Radiotherapy and Stereotactic Body Radiotherapy for Early-Stage Non-Small Cell Lung Cancer.

Lung cancer is a leading cause of cancer-related deaths worldwide. Radiotherapy is an essential treatment modality for inoperable non-small cell lung cancer (NSCLC). Stereotactic body radiotherapy (SBRT) is the standard treatment for early-stage NSCLC because of its favorable local control (LC) compared to conventional radiotherapy. Carbon ion radiotherapy (CIRT) is a kind of external beam radiotherapy characterized by a steeper dose distribution and higher biological effectiveness. Several prospective studies have shown favorable outcomes. However, there is no direct comparison study between CIRT and SBRT to determine their benefits in the management of early-stage NSCLC. Thus, we conducted a retrospective, single-institutional, and contemporaneous comparison study, including propensity score-adjusted analyses, to clarify the differences in oncologic outcomes. The 3-year overall survival (OS) was 80.1% in CIRT and 71.6% in SBRT (p = 0.0077). The 3-year LC was 87.7% in the CIRT group and 79.1% in the SBRT group (p = 0.037). Multivariable analyses showed favorable OS and LC in the CIRT group (hazard risk [HR] = 0.41, p = 0.047; HR = 0.30, p = 0.040, respectively). Log-rank tests after propensity score matching and Cox regression analyses using propensity score confirmed these results. These data provided a positive efficacy profile of CIRT for early-stage NSCLC.

Evaluation of Carbon Ion Radiation-Induced Trismus in Head and Neck Tumors Using Dose-Volume Histograms.

Carbon ion radiotherapy (C-ion RT) provides a highly localized deposition of energy that can increase radiation doses to tumors while minimizing irradiation of adjacent normal tissues. For tumors located near the temporomandibular joint, C-ion RT-induced trismus may occur. However, the relationship between the carbon ion dose and the onset of trismus is unclear. In this prospective observational study, we assessed the trismus/carbon ion dose relationship using dose-volume histograms in 35 patients who received C-ion RT in their head and neck regions between 2010 and 2014. Trismus was evaluated in patients according to the Common Terminology Criteria for Adverse Events, version 4.0. All patients were treated with 57.6 or 64.0 Gy (relative biological effectiveness (RBE)) in 16 fractions, and the median follow-up time was 57 months. Grade 2 trismus was observed in six patients. The median onset time was 12 months. At maximum radiation doses, all masticatory muscles and coronoid processes, particularly the masseter muscle, were significantly different (p = 0.003). The contouring of the masseter muscle and coronoid process requires different treatment planning. The maximum radiation doses of the coronoid process can be proposed as a guideline for treatment planning, considering the ease of contouring in C-ion RT.

Small size gold nanoparticles enhance apoptosis-induced by cold atmospheric plasma via depletion of intracellular GSH and modification of oxidative stress.

Gold nanoparticles (Au-NPs) have attracted attention as a promising sensitizer owing to their high atomic number (Z), and because they are considered fully multifunctional, they are preferred over other metal nanoparticles. Cold atmospheric plasma (CAP) has also recently gained attention, especially for cancer treatment, by inducing apoptosis through the formation of reactive oxygen species (ROS). In this study, the activity of different sized Au-NPs with helium-based CAP (He-CAP) was analyzed, and the underlying mechanism was investigated. Treating cells with only small Au-NPs (2 nm) significantly enhanced He-CAP-induced apoptosis. In comparison, 40 nm and 100 nm Au-NPs failed to enhance cell death. Mechanistically, the synergistic enhancement was due to 2 nm Au-NPs-induced decrease in intracellular glutathione, which led to the generation of intracellular ROS. He-CAP markedly induced ROS generation in an aqueous medium; however, treatment with He-CAP alone did not induce intracellular ROS formation. In contrast, the combined treatment significantly enhanced the intracellular formation of superoxide (O2• -) and hydroxyl radical (•OH). These findings indicate the potential therapeutic use of Au-NPs in combination with CAP and further clarify the role of Au-NPs in He-CAP-aided therapies.

Skin Dose Reduction by Layer-Stacking Irradiation in Carbon Ion Radiotherapy for Parotid Tumors.

Background: Layer-stacking irradiation (LSI) results in the accumulation of multiple small spread-out Bragg peaks along the beam direction. Although the superiority of LSI to conventional passive irradiation (CPI) regarding normal tissue sparing is theoretically evident, the clinical benefit of LSI has not been demonstrated. Here, we compared LSI with CPI using the same treatment planning-computed tomography images used for carbon ion radiotherapy (CIRT). Methods: Twenty-one parotid tumors were analyzed. The clinical target volume (CTV) 1 and CTV2 encompassed the parotid grand and the tumor, respectively. CTV1 and CTV2 received 36 Gy (RBE: relative biological effectiveness) in nine fractions and 64 Gy (RBE) in 16 fractions, respectively, using either LSI or CPI. CTV coverage was assessed by DX%, which is the dose covering at least X% of the target volume. Skin dose was assessed by SX, which is the skin surface area receiving at least X Gy (RBE). Results: For CTV1 and CTV2, there were no significant differences in D2% between LSI and CPI. D50% and D98% were slightly higher for CPI; however, the absolute difference between the two methods was <3%. S10-S60 (in increments of 10) were significantly lower for LSI than for CPI (P < 0.001 for all parameters). LSI was associated with a significant trend toward dose reduction at the skin area irradiated with a higher dose by CPI (P < 0.001). Conclusions: LSI achieved better skin sparing than CPI without sacrificing target volume coverage in parotid tumor patients.

A phase II study of adaptive two-step intensity-modulated radiation therapy (IMRT) with chemotherapy for loco-regionally advanced nasopharyngeal cancer (JCOG1015).

BACKGROUND: A phase II study of adaptive two-step intensity-modulated radiotherapy (IMRT) with chemotherapy for nasopharyngeal cancer (NPC) (JCOG1015) was conducted to evaluate the efficacy and safety. METHODS: Patients aged 20-75 years with stages II-IVB NPC were enrolled. As adaptive two-step IMRT, computed tomography planning was performed twice before IMRT for the initial plan of 46 Gy/23 fractions and during treatment for the boost plan of 24 Gy/12 fractions with a total dose of 70 Gy. Chemotherapy (cisplatin 80 mg/m2/3-weeks × 3 courses) was administered concurrently with IMRT, followed by adjuvant chemotherapy (cisplatin at 70 mg/m2 with 5-FU 700 at mg/m2 for 5 days/4 weeks × 3 courses). RESULTS: Between 2011 and 2014, 75 patients were enrolled from 12 institutions. The 3-year overall survival (OS) for the 75 patients was 88%, and the upper and lower limits of the 95% CI of 78%-94% were higher than the expected 3-year OS of 75% for the target population adjusted by the actual proportion of stage II:III:IV = 21%:44%:35%. The 3-year progression-free survival (PFS) and loco-regional PFS were 71% [59-80%] and 77% [66-85%], respectively. Although no grade 4-5 late toxicities were observed, 15 patients (20%) developed grade 3 late toxicities. Grade 2 xerostomia was noted in 26%, 12%, and 9% at 1, 2, and 3 years after starting IMRT, respectively. CONCLUSIONS: Adaptive two-step IMRT for NPC demonstrated an excellent 3-year OS with acceptable toxicities. This method may be one treatment option for locally advanced NPC.

Dose assessment for patients with stage I non-small cell lung cancer receiving passive scattering carbon-ion radiotherapy using daily computed tomographic images: A prospective study.

BACKGROUND AND PURPOSE: This study aimed to assess dose distributions for stage I non-small cell lung cancer (NSCLC) with passive scattering carbon-ion radiotherapy (C-ion RT) using daily computed tomography (CT) images. MATERIALS AND METHODS: We enrolled 10 patients with stage I NSCLC and acquired a total of 40 pre-fractional CT image series under the same settings as the planning CT images. These CT images were registered with planning CT images for dose evaluation using both bone matching (BM) and tumor matching (TM). Using deformable image registration, we generated accumulated doses. Moreover, the volumetric dose parameters were compared in terms of tumor coverage and lung exposure and statistical analyses were performed. RESULTS: Overall, 25% of 40 fractional dose distributions were unacceptable with BM, compared with 2.5% with TM (P < 0.001). Using BM, three patients' accumulated dose distributions were unacceptable; however, all were satisfactory with TM (P < 0.001). No differences were observed in water-equivalent path length (WEL). The required margins in patients with poor dose distribution were 5.9 and 4.4 mm for BM and TM, respectively. CONCLUSIONS: This study establishes that CT image-based TM is robust compared with conventional BM for both daily and accumulated dose distributions. The effects of changes in WEL seem to be limited. Hence, daily CT alignment is recommended for patients with stage I NSCLC receiving C-ion RT.

Prognostic significance of semi-quantitative FDG-PET parameters in stage I non-small cell lung cancer treated with carbon-ion radiotherapy.

PURPOSE: Prognostic significance of volumetric 18F-fluorodeoxyglucose (FDG) positron emission tomography/computer tomography (PET/CT) parameters in carbon-ion radiotherapy (C-ion RT) treated stage I non-small cell lung cancer, and need of histology-wise separate cut-off values for risk stratification were assessed. METHODS: Thirty-nine patients (29 men and 10 women, 71.9 ± 8.3 years) who underwent FDG PET/CT examinations before C-ion RT were retrospectively evaluated. FDG-PET parameters: standardized uptake values (SUVmax, SUVpeak, and SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), and clinicopathological variables were assessed for prognosis using Cox proportional hazards regression analysis. Mann-Whitney test compared medians of significant parameters between adenocarcinoma (AC) and squamous cell carcinoma (SCC), and Kaplan-Meier curves were plotted for median-based low- and high-risk groups. RESULTS: Median follow-up period was 44.8 months. 1/2/3-year overall survival (OS), progression-free survival (PFS) and local control (LC) rates were 94.9/84.3/70.8, 82.1/69.2/58.4 and 97.3/85.7/82.3%. Multivariate analysis revealed age (hazard ratio, HR: 1.09; 95% confidence interval, CI: 1.0-1.19, p < 0.05) and MTV (HR 4.83, 95% CI 1.21-19.27, p < 0.03) predicted OS, and only MTV predicted PFS (HR 5.3, CI 1.32-21.35, p < 0.02) independently. Compared with AC, SCC had higher MTV (median, 6.625cm3 vs 0.2 cm3, p < 0.01). Single MTV cut-off based on overall cohort was insignificant in SCC for PFS (p > 0.02); separate cut-offs of MTV, 0.2 cm3 for AC (p < 0.03) and 6.625 cm3 for SCC (p < 0.05) were relevant. CONCLUSION: Among all FDG PET/CT parameters, only MTV beared prognostic ability for stage I NSCLC treated with C-ion RT, and its histological variation may need consideration for risk-adapted therapeutic management.

Efficacy and Feasibility of Salvage Re-Irradiation with CyberKnife for In-Field Neck Lymph Node Recurrence: A Retrospective Study.

Neck lymph node (LN) recurrence in the irradiated field represents an important aspect of treatment failure after primary radiotherapy owing to the lack of a standard treatment. The aim of this study is to investigate the efficacy and safety of CyberKnife treatment for neck LN recurrence after radiotherapy. Between 2008 and 2016, 55 neck LN recurrences after radiotherapy in 16 patients were treated with CyberKnife. The median follow-up period was 17 months (range, 2-53 months). The median previous radiotherapy dose was 68 Gy (range, 50-70 Gy). The median marginal dose as equivalent dose delivered in 2-Gy fractions (α/ß = 10) was 50 Gy (range, 40-58 Gy). The one-year local control (LC) and overall survival rates were 81% and 71%, respectively. The one-year LC was higher with a target volume ≤1.0 cm3 than that with a target volume >1.0 cm3 (p = 0.006). Fatal bleeding was observed in one patient who had large (91 cm3) and widespread tumor with invasion to the carotid artery before CyberKnife treatment. CyberKnife treatment for neck LN recurrence is safe and feasible in most cases. Indication for the treatment should be carefully considered for large and widespread tumors.

Carbon-ion radiotherapy combined with chemotherapy for head and neck mucosal melanoma: Prospective observational study.

This study aimed to evaluate the efficacy of carbon-ion radiotherapy in combination with chemotherapy using dacarbazine, nimustine, and vincristine (DAV therapy) in mucosal melanoma. Twenty-one patients with clinically localized mucosal melanoma of the head and neck were enrolled. The primary endpoint was 3-year overall survival (OS). Secondary endpoints included local control, progression-free survival (PFS), and adverse event occurrence. Carbon-ion radiotherapy with a dose of 57.6-64.0 Gy (relative biological effectiveness) in 16 fractions was delivered concurrently with DAV therapy, and 2 cycles of adjuvant DAV therapy were administered every 6 weeks. The median follow-up periods were 15.5 months for all patients, and 31.2 months for 12 surviving patients. All patients had locally advanced T4a or T4b disease in the rhino-sinus area. In 16 patients (76.2%), 3 cycles of planned DAV therapy were completed. The 3-year OS and PFS rates were 49.2% and 37.0% respectively. The 3-year local control rate was 92.3%. Eleven patients (52%) developed distant metastasis, which was the most frequent pattern of the first failure. Commonly presenting acute grade 2-3 toxicities associated with radiotherapy and chemotherapy were mucositis (11 patients [53%]) and leukopenia (9 patients [43%]), which improved with conservative therapy. None of the patients developed grade 3 or greater late toxicities. Carbon-ion radiotherapy in combination with DAV therapy led to excellent local control for advanced mucosal melanoma within acceptable toxicities. The efficacy of additional DAV therapy in improving survival was weaker than expected as distant metastases still occurred frequently. Trial registration no. UMIN000007939.

Hypofractionated carbon-ion radiotherapy for stage I peripheral nonsmall cell lung cancer (GUNMA0701): Prospective phase II study.

This phase II study's aim was to confirm the efficacy and safety of hypofractionated carbon-ion radiotherapy in patients with stage I peripheral nonsmall cell lung cancer (NSCLC). The study encompassed 37 patients with histologically proven peripheral stage I NSCLC in the period June 2010-March 2015. All underwent the planned full dose of carbon-ion radiotherapy, administered with relative biological effectiveness of 52.8 Gy and 60 Gy (divided into four fractions over 1 week) for T1 and T2a tumors, respectively. The 2-year local control rate was set as the primary endpoint, while overall survival, progression-free survival, and the incidence rates of acute and late adverse events were secondary endpoints. The patients were followed up for 56.3 months overall and 62.2 months in the surviving patients, respectively. The actuarial local control rates were 91.2% after 2 years, and 88.1% after 5 years. No differences were found between the T1 and T2a tumors in the 5-year local control rate (90.9% vs 86.7%, P = .75). The actuarial overall survival rates achieved 91.9% for 2-year and 74.9% for 5-year period. T1 tumors showed actuarial 5-year overall survival rates of 80%, compared to 66.7% in T2a tumors. Two patients with T2a tumors and either severe emphysema or bronchiectasis experienced lung toxicity ≥ grade 2, in contrast to T1 patients who only experienced mild toxicities (lower than grade 2). The findings suggest that carbon-ion radiotherapy is effective and safe for peripheral stage I NSCLC; however, further clinical evaluations are needed to confirm its therapeutic efficacy. Trial registration: UMIN000003797. Registered 21 June 2010, prospectively registered.

Deep learning-assisted literature mining for in vitro radiosensitivity data.

BACKGROUND AND PURPOSE: Integrated analysis of existing radiosensitivity data obtained by the gold-standard clonogenic assay has the potential to improve our understanding of cancer cell radioresistance. However, extraction of radiosensitivity data from the literature is highly labor-intensive. To aid in this task, using deep convolutional neural networks (CNNs) and other computer technologies, we developed an analysis pipeline that extracts radiosensitivity data derived from clonogenic assays from the literature. MATERIALS AND METHODS: Three classifiers (C1-3) were developed to identify publications containing radiosensitivity data derived from clonogenic assays. C1 uses Faster Regions CNN with Inception Resnet v2 (fRCNN-IRv2), VGG-16, and Optical Character Recognition (OCR) to identify publications that contain semi-logarithmic graphs showing radiosensitivity data derived from clonogenic assays. C2 uses fRCNN-IRv2 and OCR to identify publications that contain bar graphs showing radiosensitivity data derived from clonogenic assays. C3 is a program that identifies publications containing keywords related to radiosensitivity data derived from clonogenic assays. A program (iSF2) was developed using Mask RCNN and OCR to extract surviving fraction after 2-Gy irradiation (SF2) as assessed by clonogenic assays, presented in semi-logarithmic graphs. The efficacy of C1-3 and iSF2 was tested using seven datasets (1805 and 222 publications in total, respectively). RESULTS: C1-3 yielded sensitivity of 91.2% ±â€¯3.4% and specificity of 90.7% ±â€¯3.6%. iSF2 returned SF2 values that were within 2.9% ±â€¯2.6% of the SF2 values determined by radiation oncologists. CONCLUSION: Our analysis pipeline is potentially useful to acquire radiosensitivity data derived from clonogenic assays from the literature.